BIVI - BioVie Panax Ginseng And The Treatment Of Moderate Alzheimer's Disease

Summary

• The treatment of Moderate Alzheimer's disease requires intervention after the over-activation of NMDA receptors.
• BioVie does this by reducing the phosphorlyation of ERK (Extracellular Regulatory Kinase) and by inhibiting NF-kB (Nuclear Factor-kappa Beta).
• Panax ginseng does this by inhibiting the activation of p38 MAPK (Mitogen-Activated Protein Kinase) and NF-kB (Nuclear Factor-kappa Beta).
• Panax ginseng also contains components that scavenge and partially reverse the damage that oxidants such as hydrogen peroxide and peroxynitrite do to the brain.
• It remains to be seen if BioVie's inhibition of the phosphorylation of ERK and its inhibition of NFk-B is enough to substantially alter the course of Alzheimer's disease.

I will once again use the following chart this time to discuss possible treatments for moderate Alzheimer’s disease, including BioVie’s (BIVI) NE3107 and panax ginseng.

And one more chart (derived in part from this source ): specifically for oxidative stress and neuroinflammation in Alzheimer’s disease.

NMDA receptor

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Calcium Influx

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ERK activation

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p38 MAPK activation

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NFkB and NADPH oxidase

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Inducible Nitric Oxide and Superoxide Anions? Hydrogen Peroxide early on

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Peroxynitrite (ONOO-)

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Damage to Molecules

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Toll-Like Receptor Activation

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Cytokines and other inflammatory mediators such as tumor necrosis factor-alpha, interleukins, and leukotrienes

There is an early feedback loop in Alzheimer’s disease, where hydrogen peroxide and peroxynitrite (ON00-) increases cytokine production and other inflammatory mediators which then through g protein-coupled receptors further increase the production of these oxidants. Treatments that directly inhibit these inflammatory mediators such as INmune Bio's ( INMB ) XPro1595 ( soluble tumor necrosis factor-alpha ), Annovis’s ( ANVS ) buntanetap ( via interleukin-1 and the subsequent secretion of the amyloid precursor protein ), and Montelukast (leukotrienes) may only work to some extent in early Alzheimer’s disease before the oxidation of g protein-coupled receptors. Treatments that inhibit inflammation in an upstream manner may have a positive effect on both early and later stage Alzheimer’s disease.

The key to the treatment of moderate (and perhaps severe) Alzheimer’s disease is to intervene somewhere between the over-activation of NMDA receptors and the damage following the production of peroxynitrite. One such intervention is BioVie’s NE3107 which inhibits the phosphorylation of ERK (Extracellular Regulatory Kinase) and the activation of NFk-B (Nuclear Factor kappa-Beta).

The early results for BioVie in Alzheimer’s disease and Parkinson’s disease have been promising, but these are short-term, small trials (28 days). BioVie produced a 2.2 improvement in ADAS-Cog12 scores in mild cognitive impairment, mild Alzheimer’s disease patients, and a few moderate Alzheimer's disease patients. It lead to significant improvements in motor skills for Parkinson’s disease patients when combined with Levodopa ( results and mechanism ). By inhibiting the production of oxidants (hydrogen peroxide early in the disease and peroxynitrite from there on out), NE3107 appears to help those with mild cognitive impairment and mild Alzheimer’s disease at least in the short-term, but it may also help those with moderate Alzheimer’s disease.

BioVie's stock was all over the place for a couple of weeks after the company presented results at CTAD often going up or down by double digit percentages in a single day, somewhat befitting an upstart biotech company. These days it seems to have settled down into a range between $5 and $6 a share. As of September 2022, the company had cash and short-term investments of $21.23 million and total liabilities of $16.9 million ( financial situation ). These numbers may fluctuate some until BioVie is able to complete its trials. The unanswerable question is whether BioVie’s drug slows down the above process enough to substantially effect the progression of Alzheimer’s disease (and Parkinson’s Disease).

The answer in this regards for panax ginseng is clearer. The components in panax ginseng inhibit the activation of p38 MAPK and NFk-B which limits the formation of peroxynitrite and they scavenge peroxynitrite . By doing so panax ginseng address many of the problems associated with oxidation and nitration in Alzheimer’s disease (in part by “de-oxidating” and “de-nitrating” critical receptors, transport systems, and enzyme in the brain). Here are the effects of three panax ginseng components – saponins, polysaccharides, and sinapic acid (one of several polyphenols in ginseng) - on key aspects of Alzheimer’s pathology and other neurodegenerative diseases.

Saponins

Saponins have long been recognized as key ingredients in traditional Chinese medicine. Accumulated evidence suggests that saponins have significant neuroprotective effects on attenuation of central nervous disorders, such as stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, our understanding of the mechanisms underlying the observed effects remains incomplete. Based on recently reported data from basic and clinical studies, this review highlights the proposed mechanisms of their neuroprotective function including antioxidant, modulation of neurotransmitters, anti-apoptosis [anti-death of cells], attenuating Ca(2+) influx, modulating neurotrophic factors, inhibiting tau hyperphosphorylation, and regeneration of neural networks ( study ).

Non-saponin fraction with rich polysaccharides (in a mouse model)

NFP alleviated the accumulation of A?, neuroinflammation, neuronal loss, and mitochondrial dysfunction…Moreover, NFP treatment significantly increased AHN (Adult Hippocampal Neurogenesis) ( study ).

Sinapic Acid

Our results showed that SA [sinapic acid] exhibits neuro-protection against ICV-STZ [intracerebroventricular streptozotocin] induced oxidative stress, neuro-inflammation, cholinergic dysfunction and neuronal loss, suggesting its potential in improving learning and memory in patients of AD ( study ).

The following improvements in Alzheimer’s patients administered panax ginseng seen in an open label trial and a retrospective study (in which other herbs were also used) in human beings are impressive, but not unexpected once the mechanisms of action of panax ginseng are understood. Panax ginseng/Korean Red Ginseng appears to help stabilize mild Alzheimer’s disease for at least two years (perhaps in part by inhibiting the activation of phospholipase C - PLC), and substantially slowing down the progression of moderate Alzheimer’s disease by inhibiting p38 MAPK and NFkB and by scavenging and partially reversing the oxidative and nitrostative damage done by peroxynitrite (as discussed above).

CT: conventional therapy such as Aricept and Namenda

Herbs: Mainly Panax ginseng, Rehmannia glutinosa (Chinese foxglove), Acorus tatarinowii (Grassleaf Sweetflag), Polygala tenuifolia (Chinese Milkwort), Epimedium brevicornu (Barrenwort), Cornus officinalis (Japanese Cornel Dogwood), Cistanche deserticola (Desert Broomrape), Curcuma aromatica (Aromatic curcumin), Salvia miltiorrhiza (Red Sage), Angelica sinensis (“Female Ginseng”), Gastrodia elata (Potato Orchid), and Coptis chinesis (Chinese Goldthread).

I have focused here on panax ginseng because of its multiple beneficial compounds for Alzheimer’s disease (saponins, polysaccharides, and polyphenols, for instance) and more extensive clinical trial evidence, but polyphenols in other plants may also help in the treatment of Alzheimer’s disease. Essential oils (which often contain very concentrated levels of polyphenols) that can be inhaled into the brain via aromatherapy particularly stand out in this regard ( clinical trial one , clinical trial two , case study one , case study two , case study three )

The question for BioVie is does it inhibit the phosphorylation of ERK and the activation of NFk-B enough to substantially slow down the progression of Alzheimer’s disease. Since I do not know this answer, I cannot recommend investing in the company at this point, although others who are more risk tolerant may consider doing so. Its drug is directed at two key points in the Alzheimer’s disease process. The advantage of certain plant compounds is not only do they intervene at one of these same points, they also scavenge and partially reverse the damage done by hydrogen peroxide and peroxynitrite. Treatments using natural products are frowned upon by many scientist in the United States, but they may offer even greater hope than many drug treatments.

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